Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators

被引：107

作者：

Vu, Chi B. ^{[1
]}

Bemis, Jean E. ^{[1
]}

Disch, Jeremy S. ^{[1
]}

Ng, Pui Yee ^{[1
]}

Nunes, Joseph J. ^{[1
]}

Milne, Jill C. ^{[1
]}

Carney, David P. ^{[1
]}

Lynch, Amy V. ^{[1
]}

Smith, Jesse J. ^{[1
]}

Lavu, Siva ^{[1
]}

Lambert, Philip D. ^{[1
]}

Gagne, David J. ^{[1
]}

Jirousek, Michael R. ^{[1
]}

Schenk, Simon ^{[1
]}

Olefsky, Jerrold M. ^{[1
]}

Perni, Robert B. ^{[1
]}

机构：

[1] Sirtris Pharmaceut, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 05期

关键词：

CALORIE RESTRICTION;

D O I：

10.1021/jm8012954

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.

引用

页码：1275 / 1283

页数：9

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